EGFR controls bone development by negatively regulating mTOR-signaling during osteoblast differentiation

Linder M, Hecking M, Glitzner E, Zwerina K, Holcmann M, Bakiri L, Ruocco MG, Tuckermann J, Schett G, Wagner EF, Sibilia M (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Cell Death and Differentiation Nature Publishing Group: Open Access Hybrid Model Option B

Book Volume: 25

Pages Range: 1094-1106

Journal Issue: 6

DOI: 10.1038/s41418-017-0054-7

Abstract

Mice deficient in epidermal growth factor receptor (Egfr-/- mice) are growth retarded and exhibit severe bone defects that are poorly understood. Here we show that EGFR-deficient mice are osteopenic and display impaired endochondral and intramembranous ossification resulting in irregular mineralization of their bones. This phenotype is recapitulated in mice lacking EGFR exclusively in osteoblasts, but not in mice lacking EGFR in osteoclasts indicating that osteoblasts are responsible for the bone phenotype. Experiments are presented demonstrating that signaling via EGFR stimulates osteoblast proliferation and inhibits their differentiation by suppression of the IGF-1R/mTOR-pathway via ERK1/2-dependent up-regulation of IGFBP-3. Osteoblasts from Egfr-/- mice show increased levels of IGF-1R and hyperactivation of mTOR-pathway proteins, including enhanced phosphorylation of 4E-BP1 and S6. The same changes are also seen in Egfr-/- bones. Importantly, pharmacological inhibition of mTOR with rapamycin decreases osteoblasts differentiation as well as rescues the low bone mass phenotype of Egfr-/- fetuses. Our results demonstrate that suppression of the IGF-1R/mTOR-pathway by EGFR/ERK/IGFBP-3 signaling is necessary for balanced osteoblast maturation providing a mechanism for the skeletal phenotype observed in EGFR-deficient mice.

Authors with CRIS profile

Georg Schett Lehrstuhl für Innere Medizin III

Involved external institutions

Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) ES Spain (ES) Medizinische Universität Wien AT Austria (AT) Universität Ulm DE Germany (DE)

How to cite

APA:

Linder, M., Hecking, M., Glitzner, E., Zwerina, K., Holcmann, M., Bakiri, L.,... Sibilia, M. (2018). EGFR controls bone development by negatively regulating mTOR-signaling during osteoblast differentiation. Cell Death and Differentiation, 25(6), 1094-1106. https://doi.org/10.1038/s41418-017-0054-7

MLA:

Linder, Markus, et al. "EGFR controls bone development by negatively regulating mTOR-signaling during osteoblast differentiation." Cell Death and Differentiation 25.6 (2018): 1094-1106.

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